TET2機能の回復 異常な自己再生と白血病の進行
Luisa Cimmino1, Igor Dolgalev2, Yubao Wang3
1Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Laura & Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA.
Cell
|August 22, 2017
まとめ
TET2機能の回復は白血病の幹細胞の成長を逆転させます. ビタミンCは,この効果を模倣し,PARP阻害剤に対する感受性を高めることで,TET2欠乏性がんに対する潜在的な治療を提供している.
科学分野:
- 血液学
- 癌 生物学
- エピジェネティクス
背景:
- TET2の機能喪失変異は,クローナル血液形成,骨髄分裂症候群 (MDS),急性骨髄性白血病 (AML) で一般的です.
- TET2欠乏症はDNAハイパーメチル化フェノタイプと関連しており,血液形成幹細胞および前身細胞 (HSPC) 機能に影響する.
研究 の 目的:
- TET2欠乏が白血病の幹細胞を維持する役割を調査する.
- TET2欠乏性白血病の治療戦略を探求する.
主な方法:
- Tet2の復元を研究するために,可逆性トランス遺伝子RNAiマウスモデルを生成した.
- ビタミンCのサプリメントを用いて,TET2機能をインビトロとインビボで模倣した.
- HSPCの自己更新,白血病コロニー形成,患者由来異種移植 (PDXs) に対して評価された効果
- DNAメチル化パターンと 遺伝子発現のサインを分析した
主要な成果:
- Tet2回復は,Tet2欠乏したモデルにおける異常なHSPCの自己更新を逆転させた.
- ビタミンCは5ヒドロキシメチルサイトシン形成を促進し,ヒト細胞とPDXの白血病増殖を抑制しました.
- ビタミンCはDNAヒポメチル化とTET2依存遺伝子発現を誘導した.
- ビタミンC治療はPARP抑制に白血病細胞を敏感にする.
結論:
- TET2欠乏は白血病の幹細胞維持に寄与する.
- ビタミンCはTET2を機能的に置き換えることができ,TET2欠乏性白血病に対する潜在的な治療方法を提供します.
- ビタミンCとPARP阻害剤を併用した治療は,がんにおけるTET欠乏症の治療に有望である.
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